Much of our understanding of the cellular regulation of immune responsiveness has come from studies of those "experiments of nature" the immunodeficiency diseases. The biochemical basis of most of these defects is unknown. The discovery of several children with severe combined immunodeficiency who lack the enzyme adenosine deaminase, suggest a causal relationship. Until this time no specific role of this enzyme in lymphocyte growth and differentiation had been suspected. We propose to determine the genetic and biochemical mechanisms responsible for the absence of adenosine deaminase in severe combined immunodeficiency disease. In other experiments, using animals and mutant lymphocytes in tissue culture, we will define the biochemical and immunological role of this enzyme. From these studies, we should obtain rational approaches to the pharmacologic modification of the deficient state at the molecular and cellular level, and eventually in affected patients.